EP0549796B1 - Diphenylpiperazine derivative and drug for circulatory organ containing the same - Google Patents

Diphenylpiperazine derivative and drug for circulatory organ containing the same Download PDF

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Publication number
EP0549796B1
EP0549796B1 EP91915997A EP91915997A EP0549796B1 EP 0549796 B1 EP0549796 B1 EP 0549796B1 EP 91915997 A EP91915997 A EP 91915997A EP 91915997 A EP91915997 A EP 91915997A EP 0549796 B1 EP0549796 B1 EP 0549796B1
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Prior art keywords
compound
group
carbon atoms
hydroxy
piperazine
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EP91915997A
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German (de)
French (fr)
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EP0549796A1 (en
EP0549796A4 (en
Inventor
Masato Pola Pharmaceutical R&D Laboratory Inazu
Yoshiyuki Miyata
Toshihiro Pola Pharmaceutical R&D Morimoto
Takeshi Pola Pharmaceutical R&D Yamamoto
Yuji Pola Pharmaceutical R&D Laboratory Yoshiko
Kazunori Pola Pharmaceutical R&D Harada
Yoshiharu Pola Pharmaceutical R&D Momota
Masayuki Pola Pharmaceutical R&D Yanagi
Ryoko Pola Pharmaceutical R&D Laboratory Yokota
Tetsuo Pola Pharmaceutical R&D Laboratory Katoh
Takayuki Pola Pharmaceutical R&D Namiki
Makoto Pola Pharmaceutical R&D Laboratory Kimura
Nobuyuki Pola Pharmaceutical R&D Kawakatsu
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Pola Orbis Holdings Inc
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Pola Chemical Industries Inc
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Priority to EP94104488A priority Critical patent/EP0612738A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to a novel diphenylpiperazine derivative or its salts having a strong antagonism against calcium, and to a drug for circulatory organs containing the diphenylpiperazine derivative or its salts for use in the cure and prevention of a variety of circulatory organ diseases.
  • an antagonism against calcium particularly inhibits inflow of calcium ions into cells, which is caused by excitation of a cell membrane of cardiac muscle or vascular smooth muscle, controls contraction of such muscle and promotes vasodilation.
  • a calcium antagonism therefore, is useful for the cure and prevention of hypertension, angina pectoris, cerebral circulatory disturbances and the like, and attracting attention.
  • flunarizine clinically applied as a cerebral cirulation accelerator flunarizine clinically applied as a cerebral cirulation accelerator
  • cinnarizine clinically applied as an angiotelectasis agent are known.
  • WO 90/03371 and EP-A-0 229 623 disclose N-diphenylalkylpiperazine derivatives having aralkyl substituents at the N'-position wherein the alkyl chain is intervened by oxygen or sulfur atoms. These compounds possess antihypertensive and calcium antagonistic activities.
  • DE-A-37 23 648 discloses indolyl amino alkylenepiperazine derivatives, and from DE-A-32 00 304 the corresponding indolyl oxy alkylenepiperazines are known, both exhibiting the same pharmacological activity.
  • an object of the present invention is to provide a novel compound which possesses an excellent antagonism against calcium and is useful as a drug, and a drug containing this compound for circulatory organs.
  • the present invention relates to a diphenylpiperazine derivative represented by the following general formula (1) or its salts and a drug for circulatory organs, containing this compound as an active ingredient:
  • R 1 and R 2 are the same or different and independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a nitro group, an amino group, a hydroxy group, an optionally esterified carboxyl group selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl, or a trifluoromethyl group;
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arakyl group selected from benzyl, phenylethyl, methylbenzyl and naphthylmethyl, an acyl group selected from acetyl, propionyl, butyryl, be
  • examples of the halogen atom include a fluorine atom, chlorine atom, iodine atom, bromine atom.
  • examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, octyl, nonyl, decyl, cyclopentyl, and cyclohexyl.
  • alkoxyl group having 1 to 8 carbon atoms examples include methoxyl, ethoxyl, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, cyclopentyloxy and cyclohexyloxy.
  • Examples of the aryl group include a phenyl which may have one or more substituents (such as halogen, alkyl, alkoxyl, hydroxy, amino and the like).
  • Examples of the aryloxyl group include a phenoxyl group.
  • Examples of the aralkyloxyl group include a benzyloxy group.
  • Examples of the substituted sulfonyl group include a methanesulfonyl group and p-toluenesulfonyl group.
  • R 1 and R 2 are hydrogen and halogen, and for R 3 , hydrogen, alkyl, alkanoyl, nitro or benzyl.
  • Salts of the diphenylpiperazine derivatives represented by the general formula (1) are not particularly limited so far as they are pharmacologically acceptable, and, for example, acid addition salts and quaternary ammonium salts are mentioned.
  • organic and inorganic acids can be used.
  • organic acid include acetic acid, fumaric acid, maleic acid, citric acid, malonic acid and sufonic acids such as methylsulfonic acid and p-toluenesulfonic acid.
  • inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid.
  • Examples of compounds useful for forming a quaternary ammonium salt include alkyl halides such as methyl chloride, methyl bromide, methyl iodide, and alkylsulfuric acids such as methylsulfuric acid and dimethylsulfuric acid.
  • Such compounds represented by the general formula (1) or their salts according to the present invention can be, for instance, prepared in a conventional method in accordance with the following reaction scheme:
  • R 1 , R 2 , R 3 , Z, m and n are the same as already referred to.
  • a compound (2) and a compound (3) are reacted with each other in the presence or absence of an alkali catalyst in a solvent at room temperature or with heating, or a compound (4) and a compound (5) are reacted with each other in a solvent at room temperature or with heating to obtain the present compound (1a) wherein R 3 is a hydrogen atom.
  • the obtained compound (1a) is then reacted with an alkylating agent, an aralkylating agent, an acylating agent or a nitrating agent to obtain a compound (1b) of the present invention wherein R 3 is an alkyl group, an aralkyl group, an acyl group or a nitro group.
  • alkali catalyst useful in the reaction between the compounds (2) and (3) examples include potassium carbonate and sodium carbonate.
  • Examples of the solvent useful in the reaction between the compounds (2) and (3) or the compounds (4) and (5) include lower alcohols and dimethylformamide (hereinafter referred to as "DMF").
  • Examples of the reagent to be reacted with the compound (1a) include a combination of an alkyl halide or an aralkyl halide and a strong acid; acyl halides; acid anhydride - pyridine; and an acetic anhydride - concentrated nitric acid mixture.
  • esterified carboxyl group or an esterified carboxymethyl group is present as a substituent in the compound (1)
  • elimination of the ester residue can be achieved by hydrolyzing the compound (1) according to a conventional method.
  • conventional methods for preparing an acid addition salt of amine compounds or for preparing quaternary ammonium salts can be applied.
  • an acid addition salt an acid is added to an organic solvent solution of the compound (1).
  • the crude product of the compound (1) of the present invention or its salts is refined by recrystallization, thin-layer chromatography, column chromatography, flush chromatography, fractional high pressure liquid chromatography or the like to obtain a pure compound (1) or its salts.
  • the thus obtained compound (1) of the present invention possesses an excellent antagonism against calcium and high safety and hence is useful for the prevention and cure of a variety of diseases as a drug for circulatory organs.
  • the drugs for circulatory organs of the present invention contain compound (1) of the present invention singly or as a mixture of two or more as an active ingredient or ingredients. These drugs are mixed with liquid or solid auxiliary components, which include an excipient, a binder and a diluent, so that drugs in the form of powder, granule, tablets, capsules, solution, injection or any other physical forms can be prepared and dosed orally or non-orally.
  • liquid or solid auxiliary components which include an excipient, a binder and a diluent, so that drugs in the form of powder, granule, tablets, capsules, solution, injection or any other physical forms can be prepared and dosed orally or non-orally.
  • the oral dose for an adult is preferably 10 to 1000 mg a day in terms of the compound (1), which may be divided into several times.
  • the drug can be mixed with other medicaments or agents when dosing the same, if necessary.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 2 g of the subject compound as yellow crystals.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 1.2 g of the subject compound as white crystals.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 1.5 g of the subject compound as white crystals.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 3.05 g of the subject compound in a viscous liquid state.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 1.2 g of the subject compound in a viscous liquid state.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
  • the obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
  • reaction liquid was poured into 200 ml of cold 0.5N sodium hydroxide and the mixture was extracted with ether (50 ml x 3). The whole ether layers were combined and washed with water (50 ml x 3) and a saturated saline solution (50 ml). After drying over anhydrous sodium sulfate, the solvent was removed from the mixture by distillation. The residue of oily substance was washed three times with n-hexane according to the decantation method and was dried under reduced pressure to obtain 2.00 g of the subject compound as an yellowish solid (Yield: 66.0%).
  • the calcium antagonism was indicated by the concentration (M) of a testing agent which inhibits 50% of the maximum contraction of concentration-dependent-contraction (10 - 60 mM) of KCl, and the results were shown in Table 1.
  • Compound No. 50% inhibitory concentration (M) 3 1.3 x 10 -6 4 1.3 x 10 -6 5 1.2 x 10 -6 6 2.2 x 10 -7 Flunarizine 1.6 x 10 -6
  • mice of 4 week old Male ICR mice of 4 week old were bought, and after approximately 10 days preliminary breeding, the mice were provided for the test. The mice were fasted for 16 hours from the day before the test.
  • the testing drugs were dissolved in soybean oil, in an amount of 0.2 ml drug per 10 g of the weight of a mouse, and a compulsory oral dosing was conducted by using a metal stomach probe.
  • For the control group only soybean oil was given.
  • the observation period after the dosing was 14 days, and from the survival rate after the 14 days, the LD 50 value was calculated according to the Richfield-Wilcoxon method.
  • Compound 1 milk sugar and corn starch were screened through a sieve of #60, and after mixing uniformly, the mixture was put in a kneader. A solution of hydroxypropylcellulose was added to the kneader, and the mixture was kneaded. Then, the mixture was sieved through a sieve of #18 and was dried with air blow at 50°C. After drying the mixture, the particle size of the mixture was regulated to give a granule, and 500 mg of granule was wrapped in each wrapper.
  • the components were finely powdered, and after sufficiently mixed to give a uniform mixture, the mixture was put in gelatin capsules for oral use, each capsule containing 0.2 g mixture.
  • Compound 3 milk sugar and corn starch were screened through a sieve of #60, and after mixing uniformly, the mixture was put in a kneader. A solution of hydroxypropylcellulose was added to the kneader, and the mixture was kneaded. Then, the mixture was dried with air blow at 50°C. After drying the mixture, the particle size of the mixture was regulated through a sieve of #16, and then magnesium stearate was added and uniformly mixed. The mixture was processed by a tableting machine to obtain a tablet having a weight of 200 mg and a diameter of 8 mm.
  • the diphenylpiperazine derivatives according to the present invention possess excellent calcium antagonism and less side effect.
  • drugs for circulatory organs containing the diphenylpiperazine derivative as an active ingredient, are quite useful for the cure and prevention of a variety of circulatory organ diseases such as hypertension, angina pectoris, cerebral circulatory disturbances, arrhythmia, and the like.

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Abstract

A diphenylpiperazine derivative represented by general formula (1), salt thereof, and drug for the circulatory organs containing the same as the active ingredient: <CHEM> wherein R<1> and R<2> may be the same or different from each other and each represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, optionally esterified carboxyl or trifluoromethyl; R<3> represents hydrogen, alkyl, aralkyl, acyl, nitro or optionally esterified carboxymethyl; Ar represents phenyl or naphthyl which may have one to three substituents such as halogen, alkyl, alkoxy, aryloxy, aralkyloxy, nitro, amino, cyano, acyl, hydroxy, optionally esterified carboxyl, substituted sulfonyl, aryl or trifluoromethyl; Z represents sulfur or -NR<4>- wherein R<4> represents hydrogen, alkyl, aralkyl, acyl, aryl, substituted sulfonyl or optionally esterified carboxyl; m represents a number of 1 to 5; and n represents a number of 0 to 5.

Description

The present invention relates to a novel diphenylpiperazine derivative or its salts having a strong antagonism against calcium, and to a drug for circulatory organs containing the diphenylpiperazine derivative or its salts for use in the cure and prevention of a variety of circulatory organ diseases.
Conventionally, a variety of drugs have been developed and clinically used for the cure and prevention of circulatory organ diseases. Among them, an antagonism against calcium particularly inhibits inflow of calcium ions into cells, which is caused by excitation of a cell membrane of cardiac muscle or vascular smooth muscle, controls contraction of such muscle and promotes vasodilation. A calcium antagonism, therefore, is useful for the cure and prevention of hypertension, angina pectoris, cerebral circulatory disturbances and the like, and attracting attention.
As typical examples of such a calcium antagonism, flunarizine clinically applied as a cerebral cirulation accelerator, cinnarizine clinically applied as an angiotelectasis agent, and the like are known.
WO 90/03371 and EP-A-0 229 623 disclose N-diphenylalkylpiperazine derivatives having aralkyl substituents at the N'-position wherein the alkyl chain is intervened by oxygen or sulfur atoms. These compounds possess antihypertensive and calcium antagonistic activities.
DE-A-37 23 648 discloses indolylaminoalkylenepiperazine derivatives, and from DE-A-32 00 304 the corresponding indolyloxyalkylenepiperazines are known, both exhibiting the same pharmacological activity.
It is well known, as indicated in the cited documents, that blood flowing back to ischemic circulatory organs gives rise to oxygen radicals which often damage the circulatory organs. These above-mentioned documents also state that a medicament for circulatory organs should have an ability to inhibit the formation of oxygen radicals (peroxides) which tend to arise upon the flowing back of blood. The activity of the known compounds as antioxidants is not sufficient, and the development of a new medicament which has an antagonism against calcium with less side effect has still been desired.
Accordingly, an object of the present invention is to provide a novel compound which possesses an excellent antagonism against calcium and is useful as a drug, and a drug containing this compound for circulatory organs.
Under such circumstances, the present inventors have carried out extensive studies and have found that a novel diphenylpiperazine derivative represented by general formula (1) as described hereinafter and its salts possess a strong antagonism against calcium compared with flunarizine or cinnarizine conventionally used, a less toxicity and a high safety and is widely applicable as a drug for circulatory organs.
The present invention relates to a diphenylpiperazine derivative represented by the following general formula (1) or its salts and a drug for circulatory organs, containing this compound as an active ingredient:
Figure 00040001
wherein R1 and R2 are the same or different and independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a nitro group, an amino group, a hydroxy group, an optionally esterified carboxyl group selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl, or a trifluoromethyl group; R3 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arakyl group selected from benzyl, phenylethyl, methylbenzyl and naphthylmethyl, an acyl group selected from acetyl, propionyl, butyryl, benzoyl, halogenobenzoyl and alkoxybenzoyl, a nitro group or an optionally esterified carboxymethyl group selected from methoxycarbonylmethyl, ethoxycarbonylmethyl and carboxymethyl; Ar represents a phenyl or naphthyl group which may have 1 to 3 substituents such as halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 8 carbon atoms, phenoxyl, benzyloxy, nitro, an amino, cyano, acyl selected from acetyl, propionyl, butyryl, benzoyl, halogenobenzoyl and alkoxybenzoyl, hydroxy, optionally esterified carboxyl, selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl, methanesulfonyl group, p-toluenesulfonyl group, phenyl optionally substituted by one or more of halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy and amino or trifluoromethyl; Z represents a group of -NR4- (R4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arakyl group selected from benzyl, phenylethyl, methylbenzyl and naphthylmethyl, an acyl group selected from acetyl, propionyl, butyryl, benzoyl, halogenobenzoyl and alkoxybenzoyl, phenyl optionally substituted by one or more of halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy and amino, a methanesulfonylgroup, p-toluenesulfonyl group or an optionally esterified carboxyl group selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl); m represents a number of 1 to 5, and n represents a number of 0 to 5; provided that R3, Z and n are not simultaneously a hydrogen atom and 0, respectively.
In the general formula (I), examples of the halogen atom include a fluorine atom, chlorine atom, iodine atom, bromine atom. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, octyl, nonyl, decyl, cyclopentyl, and cyclohexyl. Examples of the alkoxyl group having 1 to 8 carbon atoms include methoxyl, ethoxyl, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, cyclopentyloxy and cyclohexyloxy.
Examples of the aryl group include a phenyl which may have one or more substituents (such as halogen, alkyl, alkoxyl, hydroxy, amino and the like). Examples of the aryloxyl group include a phenoxyl group. Examples of the aralkyloxyl group include a benzyloxy group. Examples of the substituted sulfonyl group include a methanesulfonyl group and p-toluenesulfonyl group.
Among these groups, particularly preferable groups for R1 and R2 are hydrogen and halogen, and for R3, hydrogen, alkyl, alkanoyl, nitro or benzyl.
Salts of the diphenylpiperazine derivatives represented by the general formula (1) are not particularly limited so far as they are pharmacologically acceptable, and, for example, acid addition salts and quaternary ammonium salts are mentioned. In order to form a acid addition salt, organic and inorganic acids can be used. Examples of organic acid include acetic acid, fumaric acid, maleic acid, citric acid, malonic acid and sufonic acids such as methylsulfonic acid and p-toluenesulfonic acid. Examples of inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid. Examples of compounds useful for forming a quaternary ammonium salt include alkyl halides such as methyl chloride, methyl bromide, methyl iodide, and alkylsulfuric acids such as methylsulfuric acid and dimethylsulfuric acid.
As to particularly preferable examples of the diphenylpiperazine derivative represented by the general formula (1), the following compounds and their salts are given:
1-diphenylmethyl-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-methoxy-3-(N-methyl-N-phenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-acetoxy-3-(N-acetyl-N-phenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(N-methyl-N-phenylamino)-2-phenylmethyloxypropyl]piperazine, (S)-(-)-1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylaminopropyl) piperazine, (R)-(+)-1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-methylphenylamino)propyl]piperazine, 1-[(4-aminophenylamino)-2-hydroxypropyl]-1-[4,4-bis(4-fluorophenyl)butyl]piperazine, 1-[bis(4-fluorophenyl)methyl]-4-(2-hydroxy-3-phenylmethylaminopropyl)piperazine, 1-[3,3-bis(4-fluorophenyl)propyl]-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylmethylaminopropyl)piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(4-chlorophenylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(3,4-dichlorophenylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2-methoxyphenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(4-fluorophenylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-hydroxyphenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-methoxyphenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(3-methoxyphenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-acetoxy-3-phenylaminopropyl)piperazine, 1-(2,2-diphenylethyl)-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-(3,3-diphenylpropyl)-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-(4,4-diphenylbutyl)-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-[bis(4-fluorophenyl)methyl]-4-(2-hydroxy-3-phenylaminopropyl)piperazine, 1-[bis(4-fluorophenyl)methyl]-4-[2-hydroxy-3-(4-methoxyphenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(1-naphthylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2,3,4-trimethoxyphenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(3,4-dimethoxyphenylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-hydroxy-3,5-di-tert-butylphenylamino)-2-hydroxypropyl]piperazine, 1-diphenylmethyl-4-(2-hydroxypropyl-3-phenylmethylamino)piperazine, 1-diphenylmethyl-4-[2-hydroxy-3-(2-phenylethylamino)propyl]piperazine, 1-diphenymethyl-4-[2-hydroxy-3-{2-(2-methoxyphenyl)ethylamino}propyl]-piperazine, 1-[3-{2-(3,4-dimethoxyphenyl)ethylamino}-2-hydroxypropyl]-4-diphenylmethylpiperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2-phenylethylamino)-propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-nitrophenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(3-phenylpropylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(4-chlorophenylmethylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(3,4-dichlorophenylmethylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-methylphenylmethylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(4-methoxyphenylmethylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(2,3-dimethoxyphenylmethylamino)-2- hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2,3,4-trimethoxyphenylmethylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-methyl-N-phenylamino)propyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-phenyl-N-phenylmethylamino)propyl]piperazine, 1-[3-(N-acetyl-N-phenylamino)-2-hydroxypropyl]-4-[4,4-bis(4-fluorophenyl)butyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(N-ethoxycarbonyl-N-phenylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[3-(N,N-diphenylamino)-2-hydroxypropyl]piperazine, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-methylsulfonyl-N-phenylamino)propyl]piperazine and 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-{N-(4-methylphenyl)sulfonyl-N-phenylamino}propyl]piperazine.
Such compounds represented by the general formula (1) or their salts according to the present invention can be, for instance, prepared in a conventional method in accordance with the following reaction scheme:
Figure 00120001
In this scheme, R1, R2, R3, Z, m and n are the same as already referred to.
That is, a compound (2) and a compound (3) are reacted with each other in the presence or absence of an alkali catalyst in a solvent at room temperature or with heating, or a compound (4) and a compound (5) are reacted with each other in a solvent at room temperature or with heating to obtain the present compound (1a) wherein R3 is a hydrogen atom. The obtained compound (1a) is then reacted with an alkylating agent, an aralkylating agent, an acylating agent or a nitrating agent to obtain a compound (1b) of the present invention wherein R3 is an alkyl group, an aralkyl group, an acyl group or a nitro group.
Examples of the alkali catalyst useful in the reaction between the compounds (2) and (3) include potassium carbonate and sodium carbonate.
Examples of the solvent useful in the reaction between the compounds (2) and (3) or the compounds (4) and (5) include lower alcohols and dimethylformamide (hereinafter referred to as "DMF").
Examples of the reagent to be reacted with the compound (1a) include a combination of an alkyl halide or an aralkyl halide and a strong acid; acyl halides; acid anhydride - pyridine; and an acetic anhydride - concentrated nitric acid mixture.
Further, when an esterified carboxyl group or an esterified carboxymethyl group is present as a substituent in the compound (1), the elimination of the ester residue can be achieved by hydrolyzing the compound (1) according to a conventional method. To convert the obtained compound (1) of the present invention into a salt, conventional methods for preparing an acid addition salt of amine compounds or for preparing quaternary ammonium salts can be applied. For example, to prepare an acid addition salt, an acid is added to an organic solvent solution of the compound (1).
The crude product of the compound (1) of the present invention or its salts is refined by recrystallization, thin-layer chromatography, column chromatography, flush chromatography, fractional high pressure liquid chromatography or the like to obtain a pure compound (1) or its salts.
The thus obtained compound (1) of the present invention possesses an excellent antagonism against calcium and high safety and hence is useful for the prevention and cure of a variety of diseases as a drug for circulatory organs.
The drugs for circulatory organs of the present invention contain compound (1) of the present invention singly or as a mixture of two or more as an active ingredient or ingredients. These drugs are mixed with liquid or solid auxiliary components, which include an excipient, a binder and a diluent, so that drugs in the form of powder, granule, tablets, capsules, solution, injection or any other physical forms can be prepared and dosed orally or non-orally.
Although the dosing amount of the drug is suitably increased or decreased depending on the age, weight and the condition of the patient, the oral dose for an adult is preferably 10 to 1000 mg a day in terms of the compound (1), which may be divided into several times. Further, the drug can be mixed with other medicaments or agents when dosing the same, if necessary.
EXAMPLES:
The present invention will now be described in detail with reference to the exemplary embodiments, and it should be understood that these embodiments are given only for illustration of the invention and are not intended to be limitative therefor.
Example 1: 1-Diphenylmethyl-4-(2-hydroxy-3-phenylaminopropyl)piperazine (compound 1):
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 0.93 g (0.01 mol) of aniline were refluxed with heating together with 200 ml of DMF for 21 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 4 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 2 g of the subject compound as yellow crystals.
  • 1H-NMR spectrum (δ ppm):
       2.3 - 2.7 (m, 10H), 3.0 - 3.1 (m, 1H), 3.2 - 3.3 (m, 1H), 3.9 - 4.0 (m, 1H), 4.2 (s, 1H), 6.6 - 6.8 (m, 5H), 7.1 - 7.5 (m, 10H)
  • Mass spectrum:
       402 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
  • m.p. 158 - 160°C
    • Example 2: 1-Diphenylmethyl-4-(2-hydoxy-3-phenylmethylaminopropyl)piperazine (compound 2):
    3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 1 g (0.01 mol) of benzylamine were refluxed with heating together with 200 ml of DMF for 5 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 4.8 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 1.2 g of the subject compound as white crystals.
  • 1H-NMR spectrum (δ ppm):
       2.2 - 2.7 (m, 12H), 3.7 - 3.9 (m, 3H), 4.2 (s, 1H), 7.1 - 7.5 (m, 15H)
  • Mass spectrum:
       416 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
  • m.p. 76 - 80°C
    • Example 3: 1-Diphenylmethyl-4-[2-hydroxy-3-(2-phenylethylamino)propyl]piperazine (compound 3):
    3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 1.2 g (0.01 mol) of 2-phenylethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 1.5 g of the subject compound as white crystals.
  • 1H-NMR spectrum (δ ppm):
       2.2 - 2.9 (m, 16H), 3.7 - 3.85 (m, 1H), 4.2 (s, 1H), 7.1 - 7.45 (m, 15H)
  • Mass spectrum:
       430 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
  • m.p. 114 - 115°C
    • Example 4: 1-Diphenylmethyl-4-[2-hydroxy-3-{2-(2-methoxyphenyl)ethylamino}propyl]piperazine (compound 4):
    3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 2 g (0.01 mol) of 2-(2-methoxyphenyl)ethylamine were refluxed with heating together with 200 ml of DMF for 21 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5.1 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 3.05 g of the subject compound in a viscous liquid state.
  • 1H-NMR spectrum (δ ppm):
       2.2 - 2.9 (m, 16H), 3.8 - 3.9 (m, 4H), 4.2 (s, 1H), 6.75 - 6.85 (m, 2H), 7.1 - 7.4 (m, 12H)
  • Mass spectrum:
       460 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
    • Example 5: 1-[3-{2-(3,4-Dimethoxyphenyl)ethylamino}-2-hydroxypropyl]-4-diphenylmethylpiperazine (compound 5):
    3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 2 g (0.01 mol) of 2-(3,4-dimethoxyphenyl)ethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate, and after washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5.1 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 1.2 g of the subject compound in a viscous liquid state.
  • 1H-NMR spectrum (δ ppm):
       2.2 - 2.9 (m, 16H), 2.7 - 3.85 (m, 7H), 4.2 (s, 1H), 6.7 - 6.85 (m, 2H), 7.1 - 7.4 (m, 11H)
  • Mass spectrum:
       490 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
    • Example 6: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylaminopropyl)piperazine (compound 6):
    3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 0.93 g (0.01 mol) of aniline were refluxed with heating with 200 ml of DMF for 21 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
  • 1H-NMR spectrum (δ ppm):
       1.3 - 1.5 (m, 2H), 1.9 - 2.1 (m, 2H), 2.2 - 2.8 (m, 12H), 2.95 - 3.1 (m, 1H), 3.1 - 3.3 (m, 1H), 3.8 - 4 (m, 2H), 6.5 - 6.75 (m, 5H), 6.8 - 7.2 (m, 8H)
  • Mass spectrum:
       480 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
    • Example 7: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylmethylaminopropyl)piperazine (compound 7):
    3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 1 g (0.01 mol) of benzylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
  • 1H-NMR spectrum (δ ppm):
       1.3 - 1.5 (m, 2H), 1.9 - 2 (m, 2H), 2.1 - 2.7 (m, 12H), 3 - 3.15 (m, 2H), 3.75 - 3.9 (m, 2H), 4.55 (s, 2H), 6.8 - 7 (m, 5H), 7 - 7.4 (m, 8H)
  • Mass spectrum:
       494 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
    • Example 8: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(2-phenylethylamino)propyl]piperazine (compound 8):
    3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 1.2 g (0.01 mol) of 2-phenylethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate - methanol and methylene chloride - methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
  • 1H-NMR spectrum (δ ppm):
       1.3 - 1.5 (m, 2H), 1.9 - 2.1 (m, 2H), 2.2 - 3 (m, 12H), 3 - 3.2 (m, 2H), 3.5 - 3.8 (m, 4H), 3.8 - 3.95 (m, 2H), 6.8 - 7 (m, 5H), 7 - 7.3 (m, 8H)
  • Mass spectrum:
       508 (M+H)
  • IR spectrum:
       3400, 2800, 1600, 1500, 1150 cm-1
    • Reference Example 1: 1-[4,4-BiS(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylthiopropyl)piperazine (compound 9):
    5.12 g (13.3 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine was dissolved in 100 ml of ethanol, and 6.0 g (54.5 mmol) of thiophenol was added to the mixture. The mixture was stirred for 5 hours at room temperature. The reaction mixture was poured into 100 ml of aqueous 10% sodium hydroxide solution, and after extracting with diethyl ether, the mixture was dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was removed from the mixture by distillation to obtain 5.61 g of the subject compound as an oily material (yield: 89%).
  • NMR (CDCl3, δ ppm):
       1.3 - 1.5 (m, 2H), 1.9 - 2.1 (m, 2H), 2.2 - 2.7 (m, 12H), 2.9 - 3.1 (m, 2H), 3.7 - 3.9 (m, 2H), 6.9 - 7.4 (m, 13H)
    • Reference Example 2: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylthiopropyl)piperazine·2HCl (compound 10):
    5.61 g (11.6 mmol) of the crude substance obtained in Example 9 was dissolved in 15 ml of ethanol, and 7.5 ml of 4.6N hydrochloric acid - ethanol solution was added to the mixture. The mixture was stirred for 15 minutes at room temperaure. After filtering out the insoluble matter, the mixture was washed twice with diethyl ether and was recrystallized from ethanol to obtain 5.21 g of the subject compound as white crystals (yield: 81%).
  • m.p. 174 to 176°C
  • IR (KBr tablet):
       3240, 2624 - 2348, 1603, 1508, 1439, 1222, 1159, 839, 760 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.40 - 1.60 (m, 2H), 1.99 (q, 2H, J=8 Hz), 2.90 - 3.90 (m, 14H), 3.95 (t, 1H, J=8 Hz), 4.12 (m, 1H), 7.00 - 7.17 (m, 5H), 7.17 - 7.40 (m, 8H)
    • Referential Example 1: (S)-(-)-1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine:
    250 mg (1.1 mmol) of (2R)-glycidyl tosylate was dissolved in 3 ml of dried methylene chloride, and, while stirring at room temperature, 2 ml of dried methylene chloride solution of 330 mg (1 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]piperazine and 0.4 ml (2.9 mmol) of triethylamine were successively added to the mixture. After stirring the mixture for 94.5 hours at the same temperature, the reaction liquid was poured in 10 ml of methylene chloride and 10 ml of 1N sodium hydroxide solution. The methylene chloride layer was separated, and the water layer was extracted with methylene chloride (7 ml x 2). The entire methylene chloride layers were combined and washed with a saturated saline solution (10 ml). After drying over anhydrous sodium sulfate, the solvent was removed from the mixture by distillation. The residue was treated by column chromatography (chloroform, chloroform : methanol = 100 : 1) of silica gel, and a fraction (chloroform : methanol = 100 : 1 effluent) was collected and concentrated. The residue was dissolved in 10 ml of the methylene chloride and was washed with 5 ml of 1N sodium hydroxide solution and 5 ml of a saturated saline solution, and after drying over anhydrous sodium sulfate, the solvent was removed by the distillation to obtain 123 mg of the subject compound as oily material (yield: 31.9%).
  • IR (KBr tablet):
       1604, 1508, 1225, 1160, 830 cm-1
  • NMR (CDCl3, δ ppm):
       1.37 - 1.50 (m, 2H), 1.99 (q, 2H, J=8 Hz), 2.23 - 2.80 (m, 14H), 3.05 - 3.15 (m, 1H), 3.86 (t, 1H, J=8 Hz), 6.90 - 7.05 (m, 4H), 7.10 - 7.25 (m, 4H)
  • [α] 24 / D - 7.4° (C=1.20, CHCl3)
    • Referential Example 2: (R)-(+)-1-[4,4-Bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine:
    By using (2S)-glycidyl tosylate, the subject compound was obtained as an oily material in the same manner as Referential Example 1.
  • IR (KBr tablet):
       1604, 1508, 1223, 1159, 828 cm-1
  • NMR (CDCl3, δ ppm):
       1.37 - 1.50 (m, 2H), 1.99 (q, 2H, J=8 Hz), 2.23 - 2.80 (m, 14H), 3.05 - 3.15 (m, 1H), 3.86 (t, 1H, J=8 Hz), 6.90 - 7.05 (m, 4H), 7.10 - 7.25 (m, 4H)
  • [α] 26 / D + 7.2° (C=1.28, CHCl3)
    • Example 9:
    According to the methods described in Reference Examples 1 and 2, the following compounds were obtained.
    (1) 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-methyl-N-phenylamino)propyl]piperazine (compound 9): oily substance
  • NMR (DMSO-d6, δ ppm):
       1.35 - 1.52 (m, 2H), 1.99 (q, 2H, J=8 Hz), 2.25 - 2.56 (m, 10H), 2.56 - 2.76 (m, 2H), 2.99 (s, 3H), 3.37 (d, 2H, J=9.5 Hz), 3.86 (t, 1H, J=8 Hz), 3.91 - 4.05 (m, 1H), 6.68 - 6.83 (m, 3H), 6.92 - 7.07 (m, 4H), 7.10 - 7.33 (m, 6H)
    • (2) Trihydrochloride of compound 9 (compound 10): white crystals
  • m.p. 192 - 195°C
  • IR (KBr tablet):
       3425, 3235 (shoulder), 2638 - 2450, 1603, 1509, 1222, 1158, 835 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.56 - 1.76 (m, 2H), 2.04 - 2.20 (m, 2H), 3.06 (s, 3H), 3.12 - 3.98 (m, 14H), 4.10 (t, 1H, J=8 Hz), 4.16 - 4.42 (m, 1H), 6.68 (t, 1H, J=7.3 Hz), 6.98 (d, 2H, J=7.3 Hz), 7.19 (t, 4H, J=8.6 Hz), 7.30 (t, 2H, J=7.7 Hz), 7.35 - 7.50 (m, 4H)
    • Referential Example 3: Synthesis of N-(2,3-epoxypropyl)-N-methylsulfonylaniline:
    1.7 g (0.01 mol) of N-methylsulfonylaniline was dissolved in 100 ml of methylene chloride, and 7 g (0.051 mol) of epibromohydrin was added to the mixture. To this mixture, a solution obtained by adding 12 g (0.047 mol) of tetrabutylammonium bromide and 2 g (0.05 mol) of sodium hydroxide into 5 ml of water, was gradually added. The mixture was stirred overnight. After washing three times with 50 ml of water, the methylene chloride was distilled off under reduced pressure. The obtained residue was refined by the silica gel chromatography to obtain 1.9 g of the subject compound as a light-yellowish oily material (yield: 83.7%).
  • IR (KBr tablet):
       1595, 1499, 1337, 1160 cm-1
  • NMR (CDCl3, δ ppm):
       7.27 - 7.47 (m, 5H), 3.72 - 4.13 (m, 2H), 3.15 - 3.21 (m, 1H), 2.97 (s, 3H), 2.76 - 2.80 (dd, 1H), 2.52 - 2.54 (dd, 1H)
    • Example 10: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-methylsulfonyl-N-phenylamino)propyl]piperazine (compound 11) and its dihydrochloride (compound 12):
    1.9 g (0.083 mol) of N-(2,3-epoxypropyl)-N-methylsulfonylaniline and 3.3 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]piperazine were dissolved in 100 ml of ethanol, and the mixture was stirred overnight at a room temperature. After distilling off the solvent from the reaction mixture under reduced pressure, the residue was refined by silica gel chromatography to obtain 2.8 g of a subject compound (compound 70) as a light-yellowish oily material (yield: 62%).
    1 g of the obtained compound was dissolved in absolute ethanol, and 2 ml of concentrated hydrochloric acid was added dropwise to the mixture. The solvent was distilled off from the mixture under reduced pressure to obtain 1.12 g of the subject dihydrochloride (compound 12) as a white amorphous (yield: 98.6).
    Compound 11:
  • NMR (CDCl3, δ ppm):
       7.65 - 7.31 (m, 5H), 7.17 - 7.11 (m, 4H), 7.02 - 6.87 (m, 4H), 3.88 - 3.70 (m, 3H), 3.65 - 3.48 (m, 1H), 3.01 (s, 3H), 2.47 - 2.27 (m, 12H), 2.09 - 1.93 (2H), 1.52 - 1.23 (m, 2H)
    • Compound 12:
  • IR (KBr tablet):
       2649, 2558, 2438, 1602, 1508, 1334, 1222, 1156 cm-1
  • NMR (CDCl3, δ ppm):
       7.87 - 7.27 (m, 9H), 7.04 - 7.27 (m, 4H), 4.24 - 3.31 (m, 16H), 2.97 (s, 3H), 2.15 - 2.02 (m, 2H), 1.73 (bs, 2H)
    • Referential Example 4: Synthesis of N-(2,3-epoxypropyl)-N-(4-methylphenyl)sulfonylaniline:
    To 10 ml of dried DMF suspension of 0.48 g (12.0 mmol) of sodium hydride (60%), while stirring at a room temperature in an argon gas atmosphere, a solution obtained by adding 10 ml of the dried DMF in 2.59 g (10.5 mmol) of N-(4-methylphenyl)sulfonylaniline was added dropwise in 10 minutes, and the mixture was stirred for 30 minutes under the same conditions. To this mixture, under the same conditions, a solution obtained by adding 10 ml of the dried DMF in 1.37 (10.0 mmol) of epibromohydrin was added dropwise over 10 minutes, and the mixture was stirred for 22 hours under the same conditions. Then, the reaction liquid was poured into 200 ml of cold 0.5N sodium hydroxide and the mixture was extracted with ether (50 ml x 3). The whole ether layers were combined and washed with water (50 ml x 3) and a saturated saline solution (50 ml). After drying over anhydrous sodium sulfate, the solvent was removed from the mixture by distillation. The residue of oily substance was washed three times with n-hexane according to the decantation method and was dried under reduced pressure to obtain 2.00 g of the subject compound as an yellowish solid (Yield: 66.0%).
  • m.p. 75 to 78°C
  • IR (KBr tablet):
       1594, 1493, 1343, 1164, 1093, 1065, 863 cm-1
  • NMR (CDCl3, δ ppm):
       2.36 - 2.48 (m, 1H), 2.39 (s, 3H), 2.67 - 2.73 (m, 1H), 3.08 - 3.18 (m, 1H), 3.58 - 3.77 (m, 2H), 7.03 - 7.13 (m, 2H), 7.20 - 7.36 (m, 5H), 7.44 - 7.54 (m, 2H)
    • Example 11: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydoxy-3-{N-(4-methylphenyl)sulfonyl-N-phenylamino}propyl]piperazine (compound 13) and its dihydrochloride (compound 14):
    By using the compound obtained in Referential Example 4, subject compounds were obtained in the same manner as Example 10.
    Compound 13: oily substance
  • NMR (CDCl3, δ ppm):
       1.31 - 1.46 (m, 2H), 1.98 (q, 2H, J=8 Hz), 2.20 - 2.39 (m, 8H), 2.41 (s, 3H), 2.46 - 2.60 (m, 4H), 3.59 (d, 2H, J=6 Hz), 3.64 - 3.77 (m, 1H), 3.85 (t, 1H, J=8 Hz), 6.95 (tt, 3H, J=2.5, 9 Hz), 7.01 - 7.09 (m, 2H), 7.09 - 7.19 (m, 4H), 7.19 - 7.33 (m, 6H), 7.45 (d, 2H, J=8.5 Hz)
    • Compound 14: white crystals
  • m.p. 132 - 136°C
  • IR (KBr tablet):
       3440, 3330, 3299, 2643 - 2437, 1625 (shoulder), 1601, 1508, 1454, 1335, 1223, 1161, 835, 823 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.55 - 1.77 (m, 2H), 2.05 - 2.2 (m, 2H), 2.49 (s, 3H), 3.00 - 3.95 (m, 14H), 3.95 - 4.05 (m, 1H), 4.11 (t, 1H, J=8 Hz), 7.10 - 7.27 (m, 6H), 7.27 - 7.57 (m, 11H)
    • Example 12:
    In the same manner as Example 10, the following compounds were obtained.
    (1) 1-[3-(N-acetyl-N-phenylamino)-2-hydroxypropyl]-4-[4,4-bis(4-fluorophenyl)butyl]piperazine (compound 15): oily substance
  • NMR (CDCl3, δ ppm):
       1.31 - 1.47 (m, 2H), 1.86 (s, 3H), 1.90 - 2.05 (m, 2H), 2.20 - 2.47 (m, 10H), 2.47 - 2.63 (m, 2H), 3.60 - 4.00 (m, 4H), 6.88 - 7.00 (m, 4H), 7.07 - 7.20 (m, 4H), 7.20 - 7.28 (m, 2H), 7.28 - 7.46 (m, 3H)
    • (2) Dihydrochloride of compound 15 (compound 16): white crystals
  • m.p. 182 - 185°C
  • IR (KBr tablet):
       3400, 3275 (shoulder), 2650 - 2464, 1651, 1594, 1508, 1223, 833 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.53 - 1.74 (m, 2H), 1.80 (s, 3H), 2.00 - 2.22 (m, 2H), 3.00 - 4.05 (m, 14H), 4.11 (t, 1H, J=8 Hz), 4.16 - 4.30 (m, 1H), 7.20 (t, 4H, J=9 Hz), 7.30 - 7.50 (m, 5H), 7.50 - 7.63 (m, 4H)
    • (3) 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-(N,N-diphenylamino)-2-hydroxypropyl]piperazine (compound 17): oily substance
  • NMR (CDCl3, δ ppm):
       1.30 - 1.45 (m, 2H), 1.90 - 2.10 (q, 2H), 2.20 - 2.45 (m, 10H), 2.45 - 2.60 (m, 2H), 3.70 - 3.75 (m, 2H), 3.83 (t, 1H), 3.95 - 4.10 (m, 1H), 6.90 - 7.00 (m, 6H), 7.05 (d, 4H), 7.05 - 7.15 (m, 4H), 7.20 (t, 4H)
    • (4) Dihydrochloride of compound 17 (compound 18): white crystals
  • m.p. 104 - 112°C
  • IR (KBr tablet):
       3330, 2923, 2560, 2366, 1595, 1502, 1450, 1225, 1159, 832, 755, 699 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.60 - 1.70 (m, 2H), 1.90 - 2.20 (q, 2H), 3.00 - 3.90 (m, 14H), 4.03 (t, 1H), 4.20 - 4.30 (m, 1H), 6.90 - 7.00 (t, 2H), 7.00 - 7.15 (m, 8H), 7.20 - 7.40 (m, 8H)
    • (5) 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-phenyl-N-phenylmethylamino)propyl]piperazine (compound 19): oily substance
  • NMR (CDCl3, δ ppm):
       1.30 - 1.50 (m, 2H), 1.90 - 2.05 (q, 2H), 2.20 - 2.50 (m, 10H), 2.50 - 2.70 (d, 2H), 3.85 (t, 1H), 4.00 - 4.10 (m, 1H), 4.66 (d, 2H), 6.65 - 6.80 (m, 3H), 6.90 - 7.00 (m, 4H), 7.00 - 7.30 (m, 11H)
    • (6) Trihydrochioride of compound 19 (compound 20): white crystals
  • m.p. 112 - 118°C
  • IR (KBr tablet):
       3554, 3411, 2565, 1602, 1506, 1225, 832 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.50 - 1.70 (m, 2H), 2.00 - 2.15 (m, 2H), 3.00 - 3.90 (m, 14H), 4.03 (t, 1H), 4.40 - 4.50 (m, 1H), 4.67 (s, 2H), 6.62 (t, 1H), 6.79 (d, 2H), 7.00 - 7.40 (m, 15H)
    • (7) 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-(N-ethoxycarbonyl-N-phenylamino)-2-hydroxypropyl]piperazine (compound 21): oily substance
  • NMR (CDCl3, δ ppm):
       1.1 - 1.3 (t, 3H, J=6.9 Hz), 1.3 - 1.5 (m, 2H), 1.9 - 2.1 (q, 2H), 2.2 - 2.7 (m, 14H), 3.5 - 4.0 (m, 2H), 4.14 (q, 2H, J=6.9 Hz), 6.9 - 7.5 (m, 13H)
    • (8) Dihydrochloride of compound 21 (compound 22): white crystals
  • IR (KBr tablet):
       3420, 2560, 1510, 1220, 1160, 830 cm-1
  • NMR (DMSO-d6, δ ppm):
       1.1 - 1.3 (t, 3H, J=6.9 Hz), 1.6 - 1.8 (m, 2H), 2.1 - 2.2 (q, 2H, J=7.6 Hz), 2.9 - 3.9 (m, 14H), 4.1 - 4.3 (m, 4H), 7.1 - 7.5 (m, 13H)
    • Test Example 1: Antagonism against calcium:
    A test for antagonism against calcium of a diphenylpiperazine derivative according to the present invention and flunarizine was carried out as follows.
    Male Wistar rats (300-350g) were exsanguinated to death and submitted to thoracotomy to take off aortae. Ring specimens having a width of 3 to 4 mm were prepared from the aortae. The specimen was suspended in a Magnus tube which was filled with Krebs Henseleit liquid of 37 ± 0.5°C, aerated with a mixing gas (95% of O2 and 5% of CO2) flowing in the liquid. A load of approximately 2 g was given to the specimen, and a tension variation was isometrically recorded.
    The calcium antagonism was indicated by the concentration (M) of a testing agent which inhibits 50% of the maximum contraction of concentration-dependent-contraction (10 - 60 mM) of KCl, and the results were shown in Table 1.
    Compound No. 50% inhibitory concentration (M)
    3 1.3 x 10-6
    4 1.3 x 10-6
    5 1.2 x 10-6
    6 2.2 x 10-7
    Flunarizine 1.6 x 10-6
    Test Example 2: Acute toxicity:
    An acute toxicity test for the diphenylpiperazine derivatives of the present invention obtained in the above-described Examples was carried out as follows.
    Male ICR mice of 4 week old were bought, and after approximately 10 days preliminary breeding, the mice were provided for the test. The mice were fasted for 16 hours from the day before the test. The testing drugs were dissolved in soybean oil, in an amount of 0.2 ml drug per 10 g of the weight of a mouse, and a compulsory oral dosing was conducted by using a metal stomach probe. For the control group, only soybean oil was given. The observation period after the dosing was 14 days, and from the survival rate after the 14 days, the LD50 value was calculated according to the Richfield-Wilcoxon method.
    As a result, for all diphenylpiperazine derivatives of the present invention indicated LD50 value of more than 1000 mg/kg.
    Preparation Example 1:
    Compound 1 24.0 g
    Milk sugar 151.1 g
    Hydroxypropylcellulose 4.9 g
    Corn starch 20.0 g
    Total 200.0 g
    Compound 1, milk sugar and corn starch were screened through a sieve of #60, and after mixing uniformly, the mixture was put in a kneader. A solution of hydroxypropylcellulose was added to the kneader, and the mixture was kneaded. Then, the mixture was sieved through a sieve of #18 and was dried with air blow at 50°C. After drying the mixture, the particle size of the mixture was regulated to give a granule, and 500 mg of granule was wrapped in each wrapper.
    Preparation Example 2:
    Compound 2 60.0 g
    Milk sugar 118.5 g
    Corn starch 20.0 g
    Talc 1.5 g
    Total 200.0 g
    The components were finely powdered, and after sufficiently mixed to give a uniform mixture, the mixture was put in gelatin capsules for oral use, each capsule containing 0.2 g mixture.
    Preparation Example 3:
    Compound 3 24.0 g
    Milk sugar 113.1 g
    Corn starch 20.0 g
    Hydroxypropylcellulose 4.9 g
    Magnesium stearate 2.0 g
    Total 200.0 g
    Compound 3, milk sugar and corn starch were screened through a sieve of #60, and after mixing uniformly, the mixture was put in a kneader. A solution of hydroxypropylcellulose was added to the kneader, and the mixture was kneaded. Then, the mixture was dried with air blow at 50°C. After drying the mixture, the particle size of the mixture was regulated through a sieve of #16, and then magnesium stearate was added and uniformly mixed. The mixture was processed by a tableting machine to obtain a tablet having a weight of 200 mg and a diameter of 8 mm.
    Industrial Applicability:
    The diphenylpiperazine derivatives according to the present invention possess excellent calcium antagonism and less side effect. Hence, drugs for circulatory organs, containing the diphenylpiperazine derivative as an active ingredient, are quite useful for the cure and prevention of a variety of circulatory organ diseases such as hypertension, angina pectoris, cerebral circulatory disturbances, arrhythmia, and the like.

    Claims (4)

    1. A process for preparing a diphenylpiperazine derivative represented by the following general formula (1) or its salts:
      Figure 00440001
      wherein R1 and R2 are the same or different and independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a nitro group, an amino group, a hydroxy group, an optionally esterified carboxyl group selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl, or a trifluoromethyl group; R3 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arakyl group selected from benzyl, phenylethyl, methylbenzyl and naphthylmethyl, an acyl group selected from acetyl, propionyl, butyryl, benzoyl, halogenobenzoyl and alkoxybenzoyl, a nitro group or an optionally esterified carboxymethyl group selected from methoxycarbonylmethyl, ethoxycarbonylmethyl and carboxymethyl; Ar represents a phenyl or naphthyl group which may have 1 to 3 substituents such as halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 8 carbon atoms, phenoxyl, benzyloxy, nitro, an amino, cyano, acyl selected from acetyl, propionyl, butyryl, benzoyl, halogenobenzoyl and alkoxybenzoyl, hydroxy, optionally esterified carboxyl, selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl, methanesulfonyl group, p-toluenesulfonyl group, phenyl optionally substituted by one or more of halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy and amino or trifluoromethyl; Z represents a group of -NR4- (R4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arakyl group selected from benzyl, phenylethyl, methylbenzyl and naphthylmethyl, an acyl group selected from acetyl, propionyl, butyryl, benzoyl, halogenobenzoyl and alkoxybenzoyl, phenyl optionally substituted by one or more of halogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy and amino, a methanesulfonylgroup, p-toluenesulfonyl group or an optionally esterified carboxyl group selected from methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and butyloxycarbonyl); m represents a number of 1 to 5, and n represents a number of 0 to 5; provided that R3, Z and n are not simultaneously a hydrogen atom and 0, respectively, which comprises reacting a compound of the formula (2)
      Figure 00450001
      and butyloxycarbonyl and a compound of the formula (3) HZ-CnH2n-Ar wherein R1, R2, Z, Ar, m and n are defined as above, with each other in the presence or absence of an alkali catalyst in a solvent at room temperature or with heating, or reacting a compound of the formula (4)
      Figure 00460001
      and a compound of the formula (5)
      Figure 00460002
      wherein R1, R2, Z, Ar, m and n are defined as above, with each other in a solvent at room temperature or with heating to obtain the compound of the formula (1a)
      Figure 00460003
      wherein R3 is a hydrogen atom, and then reacting the resulting compound of the formula (1a) with an alkylating agent, aralkylating agent, acylating agent or a nitrating agent to obtain a compound of the formula (1)
      Figure 00470001
      wherein R1, R2, R3, Z, Ar, m and n are defined as above, and optionally converting the resulting compound of the formula (1) into a salt.
    2. A process according to claim 1, wherein the alkali catalyst comprises potassium carbonate and sodium carbonate.
    3. A process according to claims 1 or 2, wherein the solvent comprises lower alcohols and dimethylformamide.
    4. A process according to claims 1, 2 or 3, wherein the compound of the formula (1a) is reacted with a combination of an alkyl halide or an aralkyl halide and a strong acid, acyl halides, acid anhydride-pyridin or an acetic anhydride-concentrated nitric acid mixture.
    EP91915997A 1990-09-13 1991-09-13 Diphenylpiperazine derivative and drug for circulatory organ containing the same Expired - Lifetime EP0549796B1 (en)

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    US20040266784A1 (en) * 1998-06-30 2004-12-30 Snutch Terrance P. Calcium channel inhibitors comprising benzhydril spaced from piperazine
    US6011035A (en) * 1998-06-30 2000-01-04 Neuromed Technologies Inc. Calcium channel blockers
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    US7186726B2 (en) * 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
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